Positional Transcriptomics Defines Regionally Restricted Sex- specific Differences Of The Vessel Wall

Cardiovascular diseases (CVDs) remain the leading causes of morbidity and mortality for both men and women, globally. Abdominal aortic aneurysm (AAA) represents a class of CVD with significant sex-stratification as disease burden is higher in males, but outcome of disease is poorer in females. Establishment of AAA is a complex process, defined by the interaction of multiple environmental influences and host regional vascular heterogeneity. While is it is known that many factors including developmental origin, local cellular diversity and regional bio-mechanical forces contribute to vascular bed specialization, the exact contribution of biological sex in vascular heterogeneity remains unknown. To elucidate the molecular contribution of sex to vascular heterogeneity of large arterial beds we performed single cell sequencing from cells isolated from 4 distinct anatomic locations of both male and female young adult mice: the carotid arteries, aortic arch, thoracic and abdominal aorta. Using this approach, we identified anatomic sex-invariant gene signatures as well as regional sex-specific gene signatures in vascular smooth muscle cells (vSMC) and used immunohistochemistry to validate these findings. Surprisingly, prominent regional-sex dependent differences were observed in vSMCs of the thoracic and abdominal aorta, consistent with sex-specific burden of aneurysm in these regions. From these sex-specific regionally restricted vSMC signatures, we identified several enriched signature genes that are likely contributors in the regulation of AAA development in mice and humans.